Stochastic population dynamics of cancer stemness and adaptive response to therapies

Abstract

Intratumoral heterogeneity can exist along multiple axes: Cancer stem cells (CSCs)/non-CSCs, drug-sensitive/drug-tolerant states, and a spectrum of epithelial–hybrid–mesenchymal phenotypes. Further, these diverse cell-states can switch reversibly among one another, thereby posing a major challenge to therapeutic efficacy. Therefore, understanding the origins of phenotypic plasticity and heterogeneity remains an active area of investigation. While genomic components (mutations, chromosomal instability) driving heterogeneity have been well-studied, recent reports highlight the role of non-genetic mechanisms in enabling both phenotypic plasticity and heterogeneity. Here, we discuss various processes underlying phenotypic plasticity such as stochastic gene expression, chromatin reprogramming, asymmetric cell division and the presence of multiple stable gene expression patterns (‘attractors’). These processes can facilitate a dynamically evolving cell population such that a subpopulation of (drug-tolerant) cells can survive lethal drug exposure and recapitulate population heterogeneity on drug withdrawal, leading to relapse. These drug-tolerant cells can be both pre-existing and also induced by the drug itself through cell-state reprogramming. The dynamics of cell-state transitions both in absence and presence of the drug can be quantified through mathematical models. Such a dynamical systems approach to elucidating patterns of intratumoral heterogeneity by integrating longitudinal experimental data with mathematical models can help design effective combinatorial and/or sequential therapies for better clinical outcomes.

Intrinsically disordered proteins and conformational noise: The hypothesis a decade later

“…Several reports in the literature have also documented reversal of the newly acquired phenotype both within, for example in acute leukemias, 45 and across lineages 46 , 47 including cancer stem cells (CSCs) to non-CSCs, drug-sensitive to drug-tolerant states, and a spectrum of epithelial-hybrid-mesenchymal phenotypes. 48 , 49 Together, these observations provide good evidence supporting the presence of transient states and the possibility of reversal of phenotypes.…”

Coupling Cell Size Regulation and Proliferation Dynamics ofC. glutamicumReveals Cell Division Based on Surface Area

“…Using a semi-analytical approach, we compare the adder strategy with the timer strategy. The timer is a widely used model to describe populations [21,[57][58][59][60] in which the timing of the cell cycle is independent of cell size. The adder, in contrast, does consider the cell size to define the probability of division.…”

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

“…These changes occur during embryogenesis (type 1 EMT), wound healing, tissue regeneration, fibrosis (type 2 EMT) and in cancer, where they contribute to cell stemness (plasticity), drug resistance, immune escape, and metastasis (type 3 EMT) ( Manfioletti and Fedele, 2022 ). EMT can be seen as a period of a bet-hedging—evolutionary cellular adaptation ( Jolly et al, 2018 ; Capp and Thomas, 2022 ; Jain et al, 2022 ), which diversifies mesenchymal phenotypes (cancer stemness) and increases their survival ( Mortezaee and Majidpoor, 2022 ) in changing hypoxia-induced pathophysiology ( Lee et al, 2020 ; Papale et al, 2020 ; Nushtaeva et al, 2023 ; Zhang et al, 2023 ).…”